Project Summary/Abstract The long-term goal of this research is to develop highly efficient synthetic methods for preparation of high- value synthetic building blocks and bioactive molecules and to advance our understanding of the associated catalytic mechanisms. Organosilanes are stable, abundant, and virtually nontoxic, and they serve as extremely important synthetic building blocks for preparation of a wide range of bioactive molecules. Despite the advances on organosilane chemistry, much less success has been achieved on broadly applicable regio-, stereo-, and chemoselective silylation of unactivated C?C and C?H bonds. The objective of this proposal is to expand the dimension of organosilicon chemistry directed toward organic synthesis by developing new synthetic methods for C?Si formation, based on understanding the underlying complex organometallic mechanisms. The objective will be accomplished through development and application of effective C?C and C?H silylation methodologies. This research program introduces three innovative synthetic strategies: Specific Aim I: develop enantioselective redox neutral umpolung C?C silylation of cyclopropanols; Specific Aim II: develop inverse polarity net oxidative C?C silylation of cyclopropanols; Specific Aim III: develop a traceless, dual C?H silylation approach to modular synthesis of a large set of chiral 3,3?-bis-silyl BINOLs and phosphorous ligands. Based on encouraging preliminary results and initial mechanistic studies, the hypothesis for Aim I is that chiral ester or catalyst-controlled enantioselective C? C activation directed by hydrosilyl acetals allows to install a silicon moiety on a hindered carbon regio- and enantioselectively, leading to a silicon-bearing tetrasubstituted carbon center. The hypothesis for Aim II is that an oxidative silylation of cyclopropanols can be achieved through formation of metallo homoenolate- enol ether [(Z)-MHEE] intermediates that further undergoes subsequent silylation. The hypothesis for Aim III is that a sequence of dual C?H silylation of BINOLs, followed by nucleophilic activation of the resulting bis-dioxasilines with a variety of nucleophiles permit 3,3?-bis-silyl binaphthols with spontaneous removal of the directing groups. The rationale is that completion will significantly improve our knowledge concerning catalytic C?H and C?C silylation strategies and provide original approaches to structural motifs including enantio-enriched cyclic silanes to access tertiary alcohols, metallo homoenolate-enol ether intermediates leading to functionalized ketones, and chiral ligand scaffolds for asymmetric synthesis. These molecules can be ultimately used for preparation of biomedically relevant targets. The expected outcome of this work is to provide high-value synthetic building blocks, substructural units of biomedically relevant targets, and silicon-containing bioactive molecules. The results will have an important positive impact because the proposed research will be imminently useful to synthetic community and medicinal chemistry areas involving the discovery and production of new therapeutic agents.